tbuckley/cabot-search huggingface dataset:
Post-acute sequelae of SARS-CoV-2 infection in patients with cancer.
Authors: Jeremy Lyle Warner, David J. James Pinato, Sanjay Mishra, Renee Maria Saliby, Clara Hwang, Shuchi Gulati, Rana R. McKay, Chris Labaki, Elizabeth A. Griffiths, Chinmay Jani, Peter Paul Yu, Andrew Jay Portuguese, Matthew Puc, Pamela Egan, Sumit Shah, Anup Kasi, Stephanie A. Berg, Daniel Blake Flora, Melissa Kate Accordino, Dimpy P Shah
Journal: Journal of Clinical Oncology (2022)

e18746 Background: Most patients with cancer and COVID-19 will survive the acute illness. The longer-term impacts of COVID-19 on patients with cancer remain incompletely described. Methods: Using COVID-19 and Cancer Consortium registry data thru 12/31/2021, we examined outcomes of long-term COVID-19 survivors with post-acute sequelae of SARS-CoV-2 infection (PASC aka “long COVID”). PASC was defined as having recovered w/ complications or having died w/ ongoing infection 90+ days from original diagnosis; absence of PASC was defined as having fully recovered by 90 days, with 90+ days of follow-up. Patients with SARS-CoV-2 re-infection and records with low quality data were excluded. Results: 858 of 3710 of included patients (23%) met PASC criteria. Median follow-up (IQR) for PASC and recovered patients was 180 (98-217) and 180 (90-180) days, respectively. The PASC group had a higher rate of baseline comorbidities and poor performance status (Table). Cancer types, status, and recent anticancer treatment were similar between the groups. The PASC group experienced a higher illness burden, with more hospitalized (83% vs 48%); requiring ICU (29% vs 6%); requiring mechanical ventilation (17% vs 2%); and experiencing co-infections (19% vs 8%). There were more deaths in the PASC vs recovered group (8% vs 3%), with median (IQR) days to death of 158 (120-272) and 180 (130-228), respectively. Of these, 9% were attributed to COVID-19; 15% to both COVID-19 and cancer; 15% to cancer; and 23% to other causes. Conversely, no deaths in the recovered group were attributed to COVID-19; 57% were attributed to cancer; and 24% to other causes (proximal cause of death unknown/missing in 38% and 19%, respectively). Cancer treatment modification was more common in the recovered group (23% vs 18%). Conclusions: Patients with underlying comorbidities, worse ECOG PS, and more severe acute SARS-CoV-2 infection had higher rates of PASC. These patients suffered more severe complications and incurred worse outcomes. There was an appreciable rate of death in both PASC and non-PASC, with cancer the dominant but not only cause in fully recovered patients. Further study is needed to understand what factors drive PASC, and whether longer-term cancer-specific outcomes will be affected.[Table: see text]
MEDB-06. Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identifies that loss of heterogeneity and induced differentiation underlies the response to CDK4/6 inhibition
Authors: Tuan Vo, Brad Balderson, Kahli Jones, Joanna Crawford, Amanda Millar, Elissa Tolson, Marc Ruitenberg, Thomas Robertson, Dharmesh Bhuva, Melissa Davis, Brandon Wainwright, Quan Nguyen, Laura Genovesi
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups on the basis of gene expression and genomic features. Single cell transcriptome studies have defined the cellular states underlying each MB subgroup, however the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and identify how cells specific to a transcriptional state or spatial location are pivotal in responses to treatment with the CDK4/6 inhibitor, Palbociclib. We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in the majority of the tumours. Additionally, we resolve in cellular resolution a distinct tumour “interface” where the tumour contacts neighbouring mouse brain consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. Our data highlight the power of this approach to characterise the response of a tumour to targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB
Predicting patient response to cancer therapy via histopathology images.
Authors: Danh-Tai Hoang, Doreen Ben-Zvi, Leandro C. Hermida, Gal Dinstag, Efrat Elis, Sanju SInha, Neelam Sinha, Ranit Aharonov, Tuvik Beker, Eric Stone, Eytan Ruppin
Journal: Journal of Clinical Oncology (2022)

e13561 Background: Histopathology has long been considered the gold standard of clinical diagnosis and prognosis in cancer. In recent years, molecular markers including tumor gene expression have proven increasingly valuable for enhancing diagnosis and precision oncology. Here we ask if we can predict tumor gene expression from its histopathology images and based on the latter, predict patient survival and treatment response. Methods: We developed DeepPT (Deep Pathology for Treatment), a deep learning framework that predicts gene expression directly from histopathology tumor images. DeepPT is composed of three main components: a pre-trained convolutional neural network model for feature extraction, an auto-encoder for feature compression, and a multiple-layer perceptron for regression. This architecture enables the model to capitalize on the similarity among the gene expressions and benefit from the advantages of multitask learning. Results: DeepPT was trained with haematoxylin and eosin stained (H&amp;E) tumor slides from lung and breast cancer patients and their corresponding gene expression profiles. The models were then used to predict gene expression from five different held-out datasets, using nested cross validation. A total of approximately 23,000 genes were considered in this study; out of these, over 99% had a positive correlation between predicted and actual values, commonly for lung and breast cancer. Furthermore, a record number of genes (2,541 and 1,197 genes for lung and breast cancer, respectively) had a correlation above 0.4, well over the results of the current state-of-the-art approach (1,550 and 786 genes, respectively). We next studied if the inferred gene expression could be used for H&amp;E-based personalized medicine. To this end, we used the predicted tumor transcriptomics generated by DeepPT as input to ENLIGHT, a platform that predicts a patient’s response to treatment from their tumor transcriptomics. We found that ENLIGHT matching scores based on DeepPT outputs were indeed associated with response to treatment. Conclusions: DeepPT is the first computational approach for building response predictors that can infer therapy response directly from whole slide images of patient biopsies. Importantly, its future application promises to make precision oncology more accessible to physicians and patients in the developing world.
Liquid biopsy of prostate-derived tumor cells enriched from seminal fluid as a non-invasive alternative to prostate biopsy: Study feasibility
Authors: C. Saitta, A. Benetti, V. Fasulo, A. Gobbo, P. Arena, E. Beatrici, G. Chiarelli, R. Contieri, A. Uleri, P.P. Avolio, N. Frego, D. Maffei, P. Diana, M. Paciotti, A. Saita, R. Hurle, G. Lughezzani, N.M. Buffi, P. Casale, G.F. Guazzoni, M. Lazzeri
Journal: European Urology (2022)
Outcomes comparison between the robot-assisted radical prostatectomy with extended pelvic lymph node dissection and neoadjuvant chemohormonal therapy without extended pelvic lymph node dissection in patients with organ confined high-risk prostate cancer
Authors: S. Hatakeyama, R. Tabata, D. Fujimori, M. Fukuda, T. Shinozaki, H. Iwamura, T. Okamoto, T. Yoneyama, S. Sato, C. Ohyama
Journal: European Urology (2022)
Results from a phase 1b study of blinatumomab-pembrolizumab combination in adults with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Pratyush Giri, Sushrut Patil, Sumita Ratnasingam, H. Miles Prince, Samuel Milliken, Javier Briones Meijide, Luke Coyle, Marjolein Van Der Poel, Carolyn M. Mulroney, Mohammed Z. H. Farooqui, Hansen Wong, Rajendra Desai, Gerhard Zugmaier, Noemi Mergen, Paul Cannell
Journal: Journal of Clinical Oncology (2022)

e19584 Background: This open-label, multicenter, phase 1b study evaluated the safety and efficacy of blinatumomab and pembrolizumab combination therapy in patients (pts) with R/R DLBCL (NCT03340766). Methods: Key inclusion criteria included adults with ECOG performance status ≤2 and life expectancy ≥12 weeks. In cycle 1, pts received a continuous intravenous (cIV) infusion of blinatumomab followed by step dosing to the target dose (TD; Table). After a 28-day treatment-free interval, cIV infusion of blinatumomab was administered for 28 days in cycle 2 with the same dose escalations as in cycle 1. Pembrolizumab 200 mg IV was administered once every 21 days starting on day 15 in cohort 1a, and on day 19 in cohorts 2a and 3a. Pts were premedicated with dexamethasone. Dose-limiting toxicities (DLT) were the primary endpoint. The maximum tolerated dose (MTD) was the highest dose level at which ≤1 of 6 or ≤2 of 10 pts experienced a DLT. Results: As of June 10, 2021, 31 pts were enrolled in cohorts 1a, 2a, and 3a (Table). DLTs occurred in 1 (10%) pt in cohort 1a (neutropenia) and 2 (40%) pts in cohort 3a (cognitive impairment, and elevated AST, ALP, and GGT levels). Treatment-emergent (TE) adverse events (AEs) were observed in 31 (100%) pts; grade ≥3 AEs occurred in 29 (94%) pts. The most frequent grade ≥3 TEAE attributed to blinatumomab was nervous system disorders (11 [35%]) and that attributed to pembrolizumab was blood and lymphatic system disorders (5 [16%]). Serious blinatumomab-related and pembrolizumab-related AEs were observed in 15 (48%) and 2 (6%) pts, respectively. Fourteen (45%) deaths occurred; none were treatment-related. Cohort 2a dose was determined as the MTD (Table). In cohort 2a, the objective response rate within 12 weeks of blinatumomab treatment was 30%; the median duration of response in responders (n = 8) was 176.5 (range: 28–680) days. Exposures of blinatumomab and pembrolizumab in this combination study were consistent with historical data for the individual agents. Conclusions: The cohort 2a dosing schedule with TD of 56 μg/day of blinatumomab was established as the MTD. The study was terminated after dose finding because the MTD of blinatumomab in combination with pembrolizumab was lower than the MTD of blinatumomab monotherapy, with no apparent efficacy gain. Clinical trial information: NCT03340766. [Table: see text]
The promising use of hospital at home in an oncology setting.
Authors: Melanie Wain Kier, Sara Lubetsky, Gabrielle Schiller, Albert L. Siu, Katherine A. Ornstein, Cardinale B. Smith
Journal: Journal of Clinical Oncology (2022)

1523 Background: Hospitalization at Home (HaH) is an emerging clinical model that delivers the essential elements of acute hospital-level care in the home and has demonstrated efficacy largely for inpatient medical conditions. Few programs have implemented HaH for patients with active cancer diagnoses. There is little data evaluating the impact of HaH on cancer outcomes, patient experience or cost effectiveness. In 2019, the Mount Sinai Health System (MSHS) expanded its HaH program to include oncology patients. Here, we describe our institution’s experience of HaH in oncology. Methods: We performed a retrospective chart review for solid tumor, myeloma and lymphoma patients at MSHS from August 2019 to November 2021 enrolled in HaH. Patient eligibility for HaH required meeting established institutional HaH admission criteria. Demographics, cancer diagnosis, social situation, indication for antecedent ED or inpatient stay, and HaH admission were extracted from the electronic medical record. Our primary endpoint was rate of successful HaH admission, with success defined as discharge from HaH for complete recovery from the acute condition or transition to hospice. We also evaluated patient social support and home resources. Results: We enrolled 19 patients with multiple myeloma (n = 7), lymphoma (n = 1), and solid tumor (n = 11). Sixty-three percent (n = 12) were male, 74% (n = 14) were age 65 or older, and 42% (n = 8) were white. Patients were enrolled in HaH either from an inpatient service (n = 15) or from the emergency room (n = 4). While on the inpatient service, 6 of the 15 patients had received chemotherapy. Post-chemotherapy monitoring was the primary reason for HaH admission. Successful HaH admissions occurred for 79% (n = 15) of patients. The mean duration of HaH admission was 4.5 days (range 1-10 days). Three patients opted to re-enroll in HaH planned care at a later point. There were no significant issues with provider home visits, access, medication delivery, lab draws, or social support. Conclusions: The MSHS Oncology HaH program successfully cared for 79% of our cohort demonstrating the functionality of expanding the program to patients with cancer. We continue to increase enrollment for oncology patients. Further studies to assess patient outcomes, cost savings, and re-hospitalization rates when compared to the standard in hospital only care for oncology patients will help determine the benefits and preferred population to utilize oncology HaH.
Risk-stratified FIT for urgent colonoscopy in Lynch syndrome: A clinical service throughout the COVID-19 pandemic.
Authors: Anne G Lincoln, Sally C Benton, Peter Sasieni, Kevin J Monahan
Journal: Journal of Clinical Oncology (2022)

10606 Background: Lynch syndrome (LS) is an inherited disorder characterized by pathogenic variants within mismatch repair genes resulting in an increased risk of colorectal cancer (CRC). In England, the fecal immunochemical test for Haemoglobin (FIT) is currently used in non-LS symptomatic and screening populations to guide subsequent colonoscopy. Herein, we report results from a national emergency clinical service implemented during the COVID-19 pandemic which used FIT to prioritize colonoscopy in LS patients while endoscopy services were limited. Methods: Regional genetic and endoscopy services across England were invited to participate. Patient eligibility was determined by 1) Diagnosis of Lynch Syndrome 2) Planned colonoscopic surveillance between 1 March 2020 and 31 March 2021. Requests for FIT testing from participating NHS Trusts were sent to the NHS Bowel Cancer Screening South of England Hub’s Research Laboratory in Surrey. The Hub sent patients a FIT kit (OC-Sensor™ (Eiken, Japan)), instructions for use, a questionnaire, and a pre-paid return envelope. Lab reports with feecal haemoglobin (f-Hb) results were returned electronically for clinical action. LS patients were risk-stratified for colonoscopy based upon the following f-Hb thresholds: (1) f-Hb ≥10µg of Haemoglobin (Hb)/g (µg/g) faeces: triaged for colonoscopy via an urgent two-week wait (2WW) pathway, (2) f-Hb ≤10µg/g: schedule patients for colonoscopy within 6-12 weeks, where local endoscopy service availability permits. Results: Fifteen centers across England participated in the clinical service from 9 th June 2020 to 31 st March 2021. An uptake rate of 64% was observed from this cohort (375/588 invites), though 21 cases were removed from analysis due to repeat FITs, insufficient sample, missing clinical data, or FIT completed after colonoscopy. Of the remaining 354 patients analyzed, 269 patients (76%) had a f-Hb of &lt;6µg/g. 6% (n=23) of patients had a f-Hb that was at or between greater than the limit of detection of the assay (≥6µg/g) yet below 10µg/g.18% (n=62) had FIT results of ≥10µg/g and met criteria for urgent colonoscopy triage via the 2WW pathway. Of the 62 urgently triaged patients, 22 had detectable adenomas, 6 had advanced adenomas (AAs), and 4 were diagnosed with CRC (table). Conclusions: The utility of FIT during the pandemic has demonstrated clinical value for LS patients requiring CRC surveillance. Further longitudinal investigation on the efficacy of FIT in people with LS is warranted and will be examined as part of the multi-center prospective research study “FIT for Lynch Syndrome” (ISRCTN15740250) which is presently recruiting patients in the UK. [Table: see text]
TRUST-II: A global phase II study for taletrectinib in <i>ROS1</i> fusion–positive lung cancer and other solid tumors.
Authors: Misako Nagasaka, Shunichi Sugawara, Chang-Min Choi, Tatsuro Okamoto, Noriko Yanagitani, Kaname Nosaki, Toshiaki Takahashi, Yutaka Fujiwara, Hidetoshi Hayashi, John Khoury, Jorge J. Nieva, A. Eli Gabayan, Luis E. Raez, Hongbin Chen, Anastasios Dimou, Nathan A. Pennell, Geoffrey Liu, Sai-Hong Ignatius Ou, Takashi Seto, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2022)

TPS8601 Background: Taletrectinib (AB-106/DS-6051b) is a next-generation, brain-penetrant, ROS1/ NTRK tyrosine kinase inhibitor (TKI) and has shown clinically meaningful effect and safety profile in ROS1+ Non-Small Cell Lung Cancer (NSCLC) patients in phase 1 studies (Fujiwara et al, Oncotarget 2018; 9(34): 23729-23737; Ou et al, JTO Clin Res Rep. 2020 Oct 21;2(1):100108). Taletrectinib has also demonstrated activity against ROS1 G2032R resistance mutation and CNS metastases in the ongoing phase 2 TRUST study (NCT04395677) in China. Also, taletrectinib has shown preliminary efficacy against NTRK positive solid tumors in an ongoing phase 2 study (NCT04617054). Methods: TRUST-II study (NCT04919811) is a phase 2, global, multicenter, open-label, single-arm multi-cohort study evaluating the efficacy and safety of taletrectinib for ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. Taletrectinib will be given at 600 mg once daily in 21-day cycle. The patients with ROS1 fusions detected by local tests are eligible to enroll with retrospective confirmation by a central laboratory. The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N = 53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N = 46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N = 10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1 positive solid tumor other than NSCLC (N = 10). The primary endpoint is objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC) assessment for cohorts 1 and 2. Key secondary endpoints include IRC-assessed duration of response, IRC-assessed intra-cranial ORR, progression free survival (PFS), overall survival (OS), and safety. This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union. Clinical trial information: NCT04919811.
Phase I clinical safety and preliminary efficacy of PD-1-mesoCAR-T cells in the treatment of malignant pleural/peritoneal mesothelioma.
Authors: Qing Xu, Zhuqing Liu, Yong Xia, Zongchang Song, Zhongzheng Zhu, Zhicai Lin, Sitong Wang
Journal: Journal of Clinical Oncology (2022)

8559 Background: Malignant pleural/peritoneal mesothelioma (MPM) is an aggressive cancer characterized by poor therapeutic response and poor survival. Programmed cell death protein-1 (PD-1)-mediated immunosuppression is believed to be associated with T cell exhaustion and dysfunction in solid tumors. We generated chimeric antigen receptor (CAR-T) cells that can secret PD-1 nanobodies and target mesothelin (PD-1-mesoCAR-T). After identifying the anti-tumor activity and cytotoxicity of PD-1-mesoCAR-T cells by pharmacokinetics and pharmacodynamics, we conducted a proof-of-concept clinical trial in the Shanghai Tenth People's Hospital affiliated to Tongji University and the Mengchao Tumor Hospital affiliated to Shanghai University to evaluate the safety and efficacy of PD-1-mesoCAR-T cells in a dose-escalation study for malignant pleural/peritoneal mesothelioma. 6 patients received one or more infusions of the CAR-T cells with prior lymphodepletion and the longest survival is up to 18 months. Methods: This open-label, single-arm, multicenter, phase 1 study was enrolled patients with pathological diagnosis with malignant mesothelioma whose mesothelin expression in immunohistochemical samples was equal or greater than 50%. Immunohistochemical samples derived from surgical tissue, puncture tissue or pleural effusion. PD-1-mesoCAR-T cells were administered intravenously ranging 1×10 6 −1.5×10 7 /kg. Safety and efficacy were assessed in response-evaluable patients (ie, patients who received at least one dose of PD-1-mesoCAR-T and had at least one post-baseline response evaluation). Results: From July 20, 2020 to January 31, 2022, 9 patients were screened and enrolled and only 6 patients were evaluable. Mesothelin positive rate in the samples of these patients were from 50% to 100%. Three patients of them had PD-L1 positive staining in specimen. All patients underwent lymphodepletion before infusion. Two of patients (33.3%) had cytokine release syndrome, which were grade 1 and grade 3, respectively. Four patients (66.7%) developed fever. Two patients (25%) had grade 3 pulmonary infection. Stable disease was sustained for ≥3 months in 5 patients; 1 exhibited complete response and one partial response on PET or CT scan. The objective response rate (ORR) was 33.3%, but increased to 66.7% in the patients with PD-L1 positive. Only one patient of these patients appeared progression of disease after infusion. All enrolled patients are alive and observed continually. Conclusions: The clinical study of 6 patients with malignant mesothelioma shows that PD-1-mesoCAR-T cells are safe and feasible, indicating a promising curative effect. Effect of the CAR-T cells on the long term survival will be observed continually. Clinical trial information: 01722149.